Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration
Menée à l'aide des données des projets "The Cancer Genome Atlas" et "Therapeutically Applicable Research to Generate Effective Treatments" et menée à l'aide de lignées cellulaires de leucémie aiguë myéloblastique, cette étude met en évidence un mécanisme par lequel la réduction de la consommation cellulaire de vitamine C, liée à la réduction du niveau d'expression du gène SLC2A3 codant pour un transporteur de glucose, favorise la progression des cellules cancéreuses et empêche la restauration de l'activité de la méthylcytosine dioxygénase Tet
Background : Vitamin C suppresses leukaemogenesis by modulating Tet methylcytosine dioxygenase (TET) activity. However, its beneficial effect in the treatment of patients with acute myeloid leukaemia (AML) remains controversial. In this study, we aimed to identify a potential predictive biomarker for vitamin C treatment in AML. Methods : Gene expression patterns and their relevance to the survival of AML patients were analysed with The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database cases. In vitro experiments were performed on AML cell lines, a SLC2A3-knockdown cell line and patient-derived primary AML cells. Results : SLC2A3 expression was significantly decreased in leukaemic blast cells. Below-median SLC2A3 expression was associated with poor overall survival. Low SLC2A3 expression was associated with less effective demethylation, and a diminished vitamin C effect in the AML and lymphoma cell lines. SLC2A3 knockdown in the KG-1 cell line decreased the response of vitamin C. In patient-derived primary AML cells, vitamin C only restored TET2 activity when SLC2A3 was expressed. Conclusion : leucémie aiguë myéloblastique could be used as a potential biomarker to predict the effect of vitamin C treatment in AML.